Anakinra Treatment Research Articles

Abstract P2141: Effect Of Anakinra On Peak Oxygen Consumption In Patients With Heart Failure With Reduced Ejection Fraction: A Meta-analysis

Background: Peak oxygen consumption(VO2) evaluates an individual's aerobic fitness level, and provides information on overall health and fitness. Prior studies on anakinra in heart failure have not evaluated VO2 specifically in the subgroup of heart failure with reduced ejection fraction(HFrEF). Our aim was to evaluate the effect of this drug in this population. Methods: We searched five databases: Embase, MEDLINE, Cochrane, Scopus, and PubMed, for RCTs evaluating the effects of Anakinra against a placebo in HFrEF. Meta-analysis was performed using RevMan 5.4 and a random-effects model was used for the analysis. Three RCTs were identified Results: The analysis of the Anakinra effect on VO2 in patients with HFrEF was determined using 3 RCTs. Most studied its effect after 2 weeks. Compared to placebo/standard treatment, anakinra was associated with a greater change in peak VO2 from baseline VO2. However, the difference between Anakinra and placebo in peak VO2 changes was not statistically significant (MD 0.07, 95% CI -0.41 to 0.56; I2 = 43%) with an overall test effect of Z = 0.29 at p = 0.77. The VE/VCO2 slope determined the effect of Anakinra on ventilatory efficiency in HF patients. Among the 3 RCTs that evaluated VE/VCO2 slope, no difference was depicted between the Anakinra treatment relative to placebo. Thus, the statistical difference was insignificant between the two groups (MD 0.70, 95% CI -0.06 to 1.46; I2 = 0%) at p = 0.07. Conclusion: Anakinra was ineffective in improving VO2 in HFrEF. Future prospective studies with longer duration of treatment and measuring performance monitoring outcomes are needed to understand the effect of this drug for such outcomes.

RETRACTED ARTICLE: IL-1RA inhibits esophageal carcinogenesis and lymphangiogenesis via downregulating VEGF-C and MMP9

Interleukin-1 receptor antagonist (IL-1RA) has been shown to play an important role in cancer progression. However, its pathogenic effects and molecular mechanism in the malignant progression of esophageal squamous cell carcinoma (ESCC) remain largely unknown. This study was designed to explore the function of IL-1RA in ESCC and determine the relationship between IL-1RA and lymph node metastasis in ESCC patients. The clinical relevance of IL-1RA in relation to the clinicopathological features and prognosis of 100 ESCC patients was analyzed. The function and underlying mechanisms of IL-1RA in the growth, invasion, and lymphatic metastasis in ESCC were explored both in vitro and in vivo. The therapeutic effect of anakinra, an IL-1 receptor antagonist, on ESCC was also evaluated in animal experiments. Downregulation of IL-1RA was observed in ESCC tissues and cells and was found to be strongly correlated with pathological stage (P = 0.034) and lymphatic metastasis (P = 0.038). Functional assays demonstrated that upregulation of IL-1RA reduced cell proliferation, migration, and lymphangiogenesis both in vitro and in vivo. Mechanistic studies revealed that overexpression of IL-1RA activated the epithelial-to-mesenchymal transition (EMT) in the ESCC cells through activation of MMP9 and regulation of the expression and secretion of VEGF-C through the PI3K/NF-κB pathway. Anakinra treatment resulted in significant inhibition of tumor growth, lymphangiogenesis, and metastasis. IL-1RA inhibits lymph node metastasis of ESCC by regulating the EMT through activation of matrix metalloproteinase 9(MMP9) and lymphangiogenesis, driven by VEGF-C and the NF-κB signaling pathway. Anakinra may be an effective drug for the inhibition of ESCC tumor formation and lymph node metastasis.

IL-1R mediated renal sensory nerve activity drives hypertension in the DOCA-Salt mouse

Clinical trials of renal denervation (RDN) have shown unanticipated changes in non-renal sympathetic activity. It has been hypothesized that this is due to ablation of sympathoexcitatory afferent renal nerves, which are overactive under conditions of renal inflammation. This study sought to investigate the interaction of the inflammatory cytokine, IL-1, and afferent renal nerves in the pathogenesis of hypertension. To test this hypothesis, we compared the effect of afferent RDN (ARDN) to the administration of the IL-1R antagonist anakinra, on the pathogenesis DOCA-salt hypertension. In addition, the combination of ARDN and anakinra treatments in DOCA-salt mice was administered to assess the degree of mechanistic overlap. 10-week-old male C57BL6/J mice were implanted with radio-telemetry probes in the carotid artery for measurement of mean arterial pressure (MAP). DOCA was administered via subcutaneous implantation of a silicon pellet containing 50 mg of DOCA. Sham mice received a drug free silicon pellet. Uni-nephrectomy, pellet insertion, salt treatment, ARDN were all performed or started on the same day. ARDN was performed through peri-axonal application of capsaicin. IL-1R antagonist anakinra was used to suppress activation of IL-1R. Anakinra (75mg/kg) was delivered via intraperitoneal injection daily 10 days post induction of hypertension. Animals in the untreated or monotherapy groups received sham RDN and/or vehicle injections. Baseline MAP was measured 3 days prior to induction of DOCA-salt hypertension by radiotelemetry. MAP increased in untreated DOCA-salt mice by 42 ± 2 mmHg (n=7) from baseline in the final week of the study. In comparison, this response was attenuated by 42% by ARDN (+24 ± 2 mmHg, n=7). IL-1α and IL-1β were both increased in DOCA-salt kidneys (112.4 ± 19.2 pg/mg and 2.1 ± 0.4 pg/mg respectively) compared to sham kidneys (31.98 ± 4.4 pg/mg and 0.36 ± 0.06 pg/mg respectively). The DOCA-salt induced increase of MAP in mice treated with anakinra alone (+23 ± 3 mmHg, n=9), or the combination of ARDN and anakinra (+26 ± 3 mmHg, n=5) was similar to ARDN monotherapy (+24 ± 2 mmHg, n=7). All treatment groups showed statistically significant changes in MAP compared to the SHAM and Vehicle treated group with 2 Way ANOVA and Tukey test for multiple comparisons. The finding that ARDN and anakinra combination therapy provides no additional benefit beyond ARDN or anakinra alone, suggests a common mechanism. We propose that antagonism of IL-1R blocks IL-1 mediated activation of afferent renal nerves resulting in decreased central sympathetic tone and decreased MAP. Further investigation into the mechanisms of cytokine mediated sensory fiber activation in the kidney are the subject of ongoing studies. T32DK083250-01A1, R01HL116476 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Effect of Interleukin-1 Antagonists on Brain Volume and Cognitive Function in Two Patients With Megalencephalic Leukoencephalopathy With Subcortical Cysts

BackgroundMegalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare leukodystrophy characterized by early-onset macrocephaly and progressive white matter vacuolation. The MLC1 protein plays a role in astrocyte activation during neuroinflammation and regulates volume decrease following astrocyte osmotic swelling. Loss of MLC1 function activates interleukin (IL)-1β-induced inflammatory signals. Theoretically, IL-1 antagonists (such as anakinra and canakinumab) can slow the progression of MLC. Herein, we present two boys from different families who had MLC due to biallelic MLC1 gene mutations and were treated with the anti-IL-1 drug anakinra. MethodsTwo boys from different families presented with megalencephaly and psychomotor retardation. Brain magnetic resonance imaging findings in both patients were compatible with the diagnosis of MLC. The diagnosis of MLC was confirmed via Sanger analysis of the MLC1 gene. Anakinra was administered to both patients. Volumetric brain studies and psychometric evaluations were performed before and after anakinra treatment. ResultsAfter anakinra therapy, brain volume in both patients decreased significantly and cognitive functions and social interactions improved. No adverse effects were observed during anakinra therapy. ConclusionsAnakinra or other IL-1 antagonists can be used to suppress disease activity in patients with MLC; however, the present findings need to be confirmed via additional research.

Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy

Chimeric antigen receptor-engineered (CAR)-T cell therapy remains limited by significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR-T therapy recipients are unknown. The primary objective of this study was to evaluate the safety of anakinra to treat refractory CRS and ICANS after CAR-T therapy. The secondary objective was to evaluate the impact of key treatment-, patient-, and disease-related variables on the time to CRS/ICANS resolution and treatment-related mortality (TRM). We retrospectively analyzed the outcomes of 43 patients with B cell or plasma cell malignancies treated with anakinra for refractory CRS or ICANS at 9 institutions in the United States and Spain between 2019 and 2022. Cause-specific Cox regression was used to account for competing risks. Multivariable cause-specific Cox regression was used to estimate the effect of anakinra dose on outcomes while minimizing treatment allocation bias by including age, CAR-T product, prelymphodepletion (pre-LD) ferritin, and performance status. Indications for anakinra treatment were grade ≥2 ICANS with worsening or lack of symptom improvement despite treatment with high-dose corticosteroids (n=40) and grade ≥2 CRS with worsening symptoms despite treatment with tocilizumab (n=3). Anakinra treatment was feasible and safe; discontinuation of therapy because of anakinra-related side effects was reported in only 3 patients (7%). The overall response rate (ORR) to CAR-T therapy was 77%. The cumulative incidence of TRM in the whole cohort was 7% (95% confidence interval [CI], 2% to 17%) at 28 days and 23% (95% CI, 11% to 38%) at 60 days after CAR-T infusion. The cumulative incidence of TRM at day 28 after initiation of anakinra therapy was 0% in the high-dose (>200 mg/day i.v.) recipient group and 47% (95% CI, 20% to 70%) in the low-dose (100 to 200 mg/day s.c. or i.v.) recipient group. The median cumulative incidence of CRS/ICANS resolution from the time of anakinra initiation was 7 days in the high-dose group and was not reached in the low-dose group, owing to the high TRM in this group. Univariate Cox modeling suggested a shorter time to CRS/ICANS resolution in the high-dose recipients (hazard ratio [HR], 2.19; 95% CI, .94 to 5.12; P=.069). In a multivariable Cox model for TRM including age, CAR-T product, pre-LD ferritin level, and pre-LD Karnofsky Performance Status (KPS), higher anakinra dose remained associated with lower TRM (HR, .41 per 1 mg/kg/day increase; 95% CI, .17 to .96; P=.039. The sole factor independently associated with time to CRS/ICANS resolution in a multivariable Cox model including age, CAR-T product, pre-LD ferritin and anakinra dose was higher pre-LD KPS (HR, 1.05 per 10% increase; 95% CI, 1.01 to 1.09; P=.02). Anakinra treatment for refractory CRS or ICANS was safe at doses up to 12 mg/kg/day i.v. We observed an ORR of 77% after CAR-T therapy despite anakinra treatment, suggesting a limited impact of anakinra on CAR-T efficacy. Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM. Prospective comparative studies are needed to confirm our findings.

Anakinra and dexamethasone treatment of idarubicin-induced mucositis and diarrhoea in rats.

Chemotherapy-induced mucositis, characterised by diarrhoea and villous atrophy, is a severe side effect contributing to reduced quality of life and premature death in cancer patients treated with cytostatics. Despite its high incidence, there is no effective supportive therapy available. The main objective of this study was to determine if the anti-inflammatory drugs anakinra and/or dexamethasone - which have different mechanism-of-action - might be used to effectively treat idarubicin-induced mucositis in rats. Mucositis was induced through a single injection with 2 mg/kg idarubicin (with saline as control), followed by daily treatments of anakinra (100 mg/kg/day), dexamethasone (10 mg/kg/day), or both during three days. After 72 hours, jejunal tissue was collected for morphological, apoptotic, and proliferative analyses, and colonic faecal water content and body weight change were determined. The diarrhoea that was induced by idarubicin (from 63.5% to 78.6% water content in faeces) was completely reversed by anakinra alone, and the jejunal villus height reduction by 36% was prevented by a combination of anakinra and dexamethasone. Dexamethasone reduced apoptosis in the jejunal crypts, both alone and in combination with anakinra. These positive effects encourage further investigations into the use of anakinra and dexamethasone as supportive therapies for chemotherapy-induced intestinal mucositis and diarrhoea.

Evaluation of Tuberculosis Risk under Interleukin-1 Inhibitor Agents in Patients with Autoinflammatory Diseases: Experience from a Region with Moderate Tuberculosis Prevalence

Abstract Background We aimed to investigate the rate of TBC reactivation in patients with autoinflammatory conditions who had been followed up under treatment with IL-1 antagonists in our clinic. We further aimed to evaluate whether latent TBC screening and isoniazid prophylaxis before IL-1 inhibitor treatment is beneficial in the prevention of reactivation. Patients and Methods This study was designed as a cross-sectional and observational study. It received the approval of the local ethics committee and was therefore performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Adult patients who had been followed up in our clinic under treatment with IL-1 antagonists were evaluated with regard to whether they had a TBC infection before and after these treatments and whether they had been screened for latent TBC infection before IL-1 antagonist treatment and received prophylaxis. Clinical and laboratory data were obtained from hospital records and via telephone interviews after the patients had given their verbal consent to participate. Results Fifty-nine patients under IL-1 antagonists were consecutively enrolled. 58 were under follow-up with the diagnosis of familial Mediterranean fever and one patient with a diagnosis of adult-onset Still’s disease. 35 patients (59.3%) were treated with anakinra and 24 (40.7%) were treated with canakinumab. 12 (50%) of the canakinumab users had previously received anakinra treatment and were switched to canakinumab due to side-effects or ineffectiveness. The number of patients who underwent latent tuberculosisc infection (LTBI) screening before treatment was 37 (62.7%); the number of patients who received prophylaxis was 13 (22%). None of the patients receiving IL-1 antagonists developed active tuberculosis. Conclusion Blocking the IL-1 pathway may be safe regarding the activation of LTBI or development of a new tuberculosis infection even in locations with a high geographical risk.

Interferon gamma-induced protein 10 (IP-10) for the early prognosis of the risk for severe respiratory failure and death in COVID-19 pneumonia.

Elevated concentrations of soluble urokinase plasminogen activator receptor (suPAR) predict progression to severe respiratory failure (SRF) or death among patients with COVID-19 pneumonia and guide early anakinra treatment. As suPAR testing may not be routinely available in every health-care setting, alternative biomarkers are needed. We investigated the performance of C-reactive protein (CRP), interferon gamma-induced protein-10 (IP-10) and TNF-related apoptosis-inducing ligand (TRAIL) for predicting SRF or death in COVID-19. Two cohorts were studied; one discovery cohort with 534 patients from the SAVE-MORE clinical trial; and one validation cohort with 364 patients from the SAVE trial including also 145 comparators. CRP, IP-10 and TRAIL were measured by the MeMed Key® platform in order to select the biomarker with the best prognostic performance for the early prediction of progression into SRF or death. IP-10 had the best prognostic performance: baseline concentrations 2000pg/ml or higher predicted equally well to suPAR (sensitivity 85.0%; negative predictive value 96.6%). Odds ratio for poor outcome among anakinra-treated participants of the SAVE-MORE trial was 0.35 compared to placebo when IP-10 was 2,000pg/ml or more. IP-10 could divide different strata of severity for SRF/death by day 14 in the validation cohort. Anakinra treatment decreased this risk irrespective the IP-10 concentrations. IP-10 concentrations of 2,000pg/ml or higher are a valid alternative to suPAR for the early prediction of progression into SRF or death the first 14days from hospital admission for COVID-19 and they may guide anakinra treatment. gov, NCT04680949 and NCT04357366.

Effectiveness Of Anakinra Therapy On Covid-19 Patients In Icu

Background: There is no consensus on effective treatments for COVID-19 disease yet. Our aim; To observe the clinical and laboratory results of anakinra treatment on intensive care patients and to contribute to the literature on its usefulness. Material and Methods: The characteristics of the patients receiving Anakinra treatment in the COVID ICU of xx were retrospectively reviewed. The patients' ages, gender, mechanical ventilation (MV) duration, length of stay in the intensive care unit, CRP, procalcitonin, LDH, IL-6, lymphocyte, Dv dimer, ferritin values and the corticosteroid doses they received in addition to Anakinra treatment were also evaluated. In addition, the data of the patient group who did not receive Anakinra but received high-dose (≥250 mg) methylprednisolone (MPZ) treatment were compared with the present patient data and evaluated in terms of treatment effectiveness. Results: When the patients that receiving Anakinra+high-dose MPZ are compared with the patient group receiving only high-dose MPZ,it was seen that the mortality rate is significantly higher (P=0.038), MV and hospitalization days in the intensive care unit were significantly longer in patients receiving Anakinra (p=0.001, p=0.004). However, there was no significant difference in secondary reproduction rates between the two groups (P=0.484). As the mean hospitalization days of the group receiving Anakinra + high-dose MPZ and the group receiving Anakinra + low-dose (<250mg) MPZ were found to be significantly longer in the group receiving Anakinra + high-dose steroids (p=0.018), there was no significant difference in terms of MV time and mortality rates (p=0.193, p=1.0). Conclusion: In our study, the patients who received Anakinra treatment had a longer hospitalization day and MV period, and the higher mortality rate was attributed to this patient group who had a more severe course. It was observed that the use of anakinra treatment after low-dose and high-dose MPZ treatment did not cause a significant difference in mortality rates. However, due to the small number of patients and the heterogeneity of the patient group, more comprehensive and randomized studies are needed.

OP33 Results of a randomised controlled trial to evaluate Interleukin 1 blockade with anakinra in patients with acute severe ulcerative colitis (IASO)

Abstract Background Acute severe ulcerative colitis (ASUC) is a severe manifestation of ulcerative colitis (UC) that requires hospitalisation. Despite significant advances in therapeutic options for UC and in the medical management of steroid-refractory ASUC, the initial treatment paradigm for ASUC has not changed since the 1950s and is based on the use of intravenous (IV) corticosteroids. Approximately 50% of patients do not respond and require further medical or surgical therapy. Interleukin 1 (IL-1) has been identified as a key mediator of colonic inflammation and plays a pivotal role in local activation of neutrophils and a number of downstream inflammatory mediators. The IL-1 axis has been repeatedly identified as a therapeutic target in UC. The Interleukin 1 (IL-1) blockade in Acute Severe Colitis (IASO) trial investigated whether antagonism of IL-1 signalling could improve outcomes in patients with ASUC. Methods We performed a phase II, multicentre randomised (1:1), placebo-controlled, double-blinded trial of IL-1 blockade with short-duration anakinra, given alongside IV corticosteroids to adult patients hospitalised with suspected or confirmed ASUC. The primary outcome was the incidence of medical (ie infliximab/ciclosporin) or surgical rescue therapy (colectomy) within 10 days following the commencement of IV corticosteroid therapy. Secondary outcomes included disease activity, time to clinical response, time to rescue therapy, colectomy incidence by day 98 post IV corticosteroids and safety. The trial aimed to recruit 214 patients across 20 sites in the UK. Prespecified analyses were performed for feasibility and for futility. Results At the time of the prespecified interim futility analysis, 113 patients had been randomised, 55 to placebo, and 58 to anakinra (figure 1). The incidence of medical or surgical rescue therapy by day 10 was higher in the anakinra group than in the placebo group (43% vs 26%). The incidence of colectomy by day 98 was higher in the anakinra group (11% vs 4%). These differences were not statistically significant. Logistic models containing a mixture of baseline stratification factors did not suggest that the need for rescue therapy would be reduced with anakinra treatment and on the advice of the independent data monitoring committee, the trial was terminated for futility. There was a higher incidence of adverse event in the placebo group, the most common was worsening of ulcerative colitis. Conclusion This trial shows that adding anakinra to current standard care with IV corticosteroids in patients with ASUC did not reduce the need for rescue therapy or colectomy. This suggests that IL-1 blockade is not a therapeutic target in ASUC. There were no safety concerns with anakinra treatment.

High-dose intravenous anakinra treatment is safe and effective in severe and critical COVID-19 patients: a propensity score-matched study in a single center.

In COVID-19, severe disease course such as need of intensive care unit (ICU) as well as development of mortality is mainly due to cytokine storm. In this study, we aimed to evaluate the high-dose intravenous anakinra treatment response and outcome in patients with severe and critically ill COVID-19 compared to standard of care. This retrospective observational study was carried out at a tertiary referral center. The study population consisted of two groups as follows: the patients receiving high-dose intravenous anakinra (anakinra group) between 01.09.2021 and 01.02.2022 and the patients treated with standard of care (SoC, control group) as historical control group who were hospitalized between 01.07.2021 and 01.09.2021. After the propensity score 1:1 matching, 79 patients in anakinra and 79 patients in SoC matched and were included into the analysis. Mean ± SD patient age was 67.4 ± 16.7 and 67.1 ± 16.3years in anakinra and SoC groups, respectively (p = 0.9). Male gender was 38 (48.7%) in anakinra and 36 (46.2%) in SoC (p = 0.8). Overall, ICU admission was in 14.1% (n = 11) and 30.8% (n = 24) (p = 0.013; OR 6.2), intubation in 12.8% (n = 10) and 16.7% (n = 13) patients (p = 0.5), and 14.1% (n = 11) and 32.1% (n = 25) patients died in anakinra and control groups, respectively (p = 0.008; OR 7.1). In our study, mortality was lower in patients receiving anakinra compared to SoC. Intravenous high-dose anakinra is safe and effective treatment in patients with severe and critical COVID-19.

The role of indices in predicting disease severity and outcomes of multisystem inflammatory syndrome in children.

The aim of this study was to evaluate the role of the systemic immune inflammation index (SII), C-reactive protein/albumin ratio (CAR), the monocyte/lymphocyte ratio (MLR), and the neutrophil/lymphocyte ratio (NLR) in predicting disease severity, treatment, and prognosis in multisystem inflammatory syndrome in children (MIS-C). This medical record review retrospectively evaluated the clinical and laboratory findings of 191 MIS-C patients followed in the Department of Pediatric Rheumatology at Ankara City Hospital, Turkey. The patients were grouped by disease severity: mild, moderate, and severe. SII, CAR, MLR, and NLR were calculated for each group. All patients had fever at the time of admission; 153 (80.1%) had gastrointestinal tract involvement, 74 (38.7%) had rash, 63 (33%) had conjunctivitis, 107 (56%) had cardiac involvement, 32 (15.6%) had renal involvement, and 143 (74.9%) had hematological involvement. According to logistic regression analysis, SII, NLR, MLR, and CAR were found to be predictive indexes for disease severity, need for intensive care, need for inotropes, and anakinra treatment in MIS-C. The cut-off values of ≥1605.3 for SII, ≥9.1 for NLR, and ≥3.9 for CAR increased the risk of severe disease by 3.4, 7.1, and 5.7 times, respectively. NLR, SII, MLR, and CAR are effective and useful for predicting the severity of MIS-C, the need for intensive care, and the need for anakinra treatment.

Detection of Inflammatory Biomarker suPAR in COVID-19 Disease With CHORUS TRIO Instrument.

Deregulation in the urokinase-type plasminogen activator receptor (uPA/uPAR) system is reported in many diseases where the immune system is activated. During SARS-CoV-2 infection, a rise in soluble uPAR (suPAR) levels has been detected and its concentration above 6 µg/L predicts worsening to severe respiratory failure 14 days earlier, with a positive predictive value of 85.9%, and was the prerequisite for a treatment with anakinra, a recombinant IL-1 receptor antagonist that blocks the activity of both IL-1α and IL-1β. To compare suPAR concentrations measured by CHORUS suPAR on CHORUS TRIO instrument of DIESSE with the commercially available suPARnostic (ViroGates) ELISA assay. A single-centre, non-pharmacological, diagnostic study was performed. A total of 522 serum samples from patients with COVID-19 were tested for suPAR. CHORUS suPAR resulted accurate and reliable, with a high grade of specificity (97.9%), accuracy (97.3%) and sensitivity (96.9%). The median concentration of suPAR, as determined with CHORUS suPAR, was 6.8 µg/L (interquartile range 4.5-9.7) in patients with moderate disease (n = 465) and 8.5 µg/L (interquartile range 5.4-10.6) in patients with severe disease. Among patients with moderate and severe disease, 60.6% and 71.9%, respectively, reached the cut-off concentration of suPAR ⩾6 µg/L, defining their illness severity and suggesting eligibility to anakinra treatment. CHORUS suPAR kit resulted as sensitive, specific, accurate and able to quantify suPAR concentrations in patients with moderate and severe COVID-19.

Efficacy and safety of early soluble urokinase plasminogen receptor plasma-guided anakinra treatment of COVID-19 pneumonia: a subgroup analysis of the SAVE-MORE randomised trial

The SAVE-MORE trial demonstrated that anakinra treatment in COVID-19 pneumonia with plasma soluble urokinase plasminogen activator (suPAR) levels of 6ng/mL or more was associated with 0.36 odds for a worse outcome compared to placebo when expressed by the WHO-Clinical Progression Scale (CPS) at day 28. Herein, we report the results of subgroup analyses and long-term outcomes. This prospective, double-blind, randomised clinical trial, recruited patients with a confirmed SARS-CoV-2 infection, in need of hospitalisation, lower respiratory tract infection and plasma suPAR ≥6ng/mL from 37 academic and community hospitals in Greece and Italy. Patients were 1:2 randomised to subcutaneous treatment with placebo or anakinra (100mg) once daily for 10 days. Pre-defined subgroups of Charlson's comorbidity index (CCI), sex, age, level of suPAR, and time from symptom onset were analysed for the primary endpoint (overall comparison of distribution of frequencies of the scores from the WHO-CPS between treatments on day 28), by multivariable ordinal regression analysis in the intention to treat (ITT) population. This trial is registered with the EU Clinical Trials Register (2020-005828-11) and ClinicalTrials.gov (NCT04680949). Patients were enrolled between 23 December 2020 and 31 March 2021; 189 patients in the placebo arm and 405 patients in the anakinra arm were the ITT population. Multivariable analysis showed that anakinra treatment was accompanied by significantly lower odds for worse outcome compared to placebo at day 28 for all studied subgroups (CCI ≥ 2, OR: 0.34, 95% confidence intervals [CI] 0.22-0.50; CCI < 2, OR: 0.38, 95% CI 0.21-0.68; suPAR > 9ng/mL, OR: 0.35, 95% CI 0.19-0.66; suPAR 6-9ng/mL, OR: 0.35, 95% CI 0.24-0.52; patients ≥65 years, OR: 0.41, 95% CI 0.25-0.66; and patients <65 years, OR: 0.29, 95% CI 0.19-0.45). The benefit was uniform, irrespective of the time from start of symptoms until the start of the study drug. At days 60 and 90, anakinra treatment had odds of 0.40 (95% CI 0.28-0.57) and 0.46 (95% CI 0.32-0.67) respectively, for a worse outcome compared to placebo. The costs of general ward stay, ICU stay, and drugs were lower with anakinra treatment. Anakinra represents an important therapeutic tool in the management of COVID-19 that may be administered in all subgroups of patients; benefits are maintained until day90. Hellenic Institute for the Study of Sepsis; Swedish Orphan Biovitrum AB.

Abstract 10389: Interleukin-1 Blockade With Anakinra Restores Cardiac Contractility Reserve and Exercise Capacity in a Mouse Model of Ischemic Heart Failure

Background: Acute myocardial infarction (AMI) is associated with an intense inflammatory response promoting adverse cardiac remodeling, impaired cardiac reserve, and reduced exercise capacity, hallmarks of heart failure. Interleukin-1β (IL-1β) is the prototypical inflammatory cytokine that is increased in AMI and is sufficient to impair cardiac reserve when administered exogenously in mice. Whether blocking IL-1β signaling with recombinant IL-1 receptor antagonist, anakinra, can restore cardiac contractile reserve and improve exercise capacity in AMI is unknown. Methods: We induced ischemic heart failure due to large non-reperfused anterior AMI in mice via surgical permanent ligation of the left anterior descending artery via lateral thoracotomy in 10-week-old male CD1 mice (N=30, 32-37 g in weight) followed for 10 weeks. Anakinra was given as intraperitoneal injection of 10 mg/kg, 0.2 ml, for three consecutive days. Cardiac contractile reserve was measured assessing changes in left ventricular fractional shortening with isoproterenol challenges (N=5). A subgroup of mice that had been previously trained to run on treadmill were used to measure interval changes in exercise capacity 10 weeks after AMI and with three consecutive days of anakinra treatment (N=6). Data are presented as mean and standard error of mean. T-test for paired group analysis was used to compare values. Results: Cardiac contractile reserve was impaired at -10±5% and restored with anakinra given for three days to +49±11% (p=0.008). Exercise capacity was also significantly reduced with AMI at 191±39 m and restored to 247±46 m after anakinra treatment (p=0.03). Conclusion: Ischemic heart failure due to large non-reperfused AMI leads to a severe reduction in cardiac contractility reserve and exercise capacity that are reversed by IL-1 blockade with anakinra.

Abstract 13994: Time to Treatment and Efficacy of IL-1 Blockade With Anakinra in ST-Segment Elevation Myocardial Infarction

Introduction: Interleukin-1 (IL-1) blockade with anakinra given within 12 hours from reperfusion has recently showed to reduce the inflammatory response as well as prevent heart failure (HF) events in patients with STEMI. Hypothesis: The aim of this study was to determine whether time to anakinra treatment influences the efficacy on systemic inflammation and HF events in patients with STEMI. Methods: This is a secondary analysis of the data from the three VCUART clinical trials, including adult patients with STEMI presenting within 12 hours of pain onset, enrolled within 12 hours of reperfusion and randomly assigned to anakinra or placebo for 14 days. We divided the cohort in two groups based on the median time from percutaneous coronary intervention (PCI) to investigational drug, and analyzed the effects of anakinra on the area-under-the-curve for C reactive protein (AUC-CRP) and on incidence of the composite endpoint of death or new onset HF. Results: We analyzed data from 139 patients: 84 (60%) treated with anakinra and 55 (40%) with placebo. The median time from PCI to investigational treatment was 271 [182-391] minutes. The AUC-CRP was significantly higher in patients receiving placebo versus anakinra both in those with from PCI to treatment &lt;271 min (222.6 [103.9-325.2] vs 78.4 [44.3-131.2], p&lt;0.001) and those with time from PCI to drug ≥271 min (235.2 [131.4-603.4] vs 75.5 [38.9-171.9, p&lt;0.001]. Anakinra significantly reduced the combined endpoint of death or new onset HF in patients with time from PCI to treatment &lt;271 min (5 [11%] vs 9 [36%], log-rank p value=0.014) as well as in patients with time from PCI to drug ≥271 min (2 [5%] vs 7 [23%], log-rank p value= 0.046). Conclusions: In patients with STEMI treated with anakinra within 12 hours of reperfusion, the therapeutic window of IL-1 blockade on the systemic inflammatory response and on HF events in reperfused STEMI appears to be stable for several hours.

Comparison of Anakinra and Tocilizumab in Anticytokine Therapy in the Treatment of Coronavirus Disease-2019.

It is known that coronavirus disease-2019 (COVID-19) pneumonia causes cytokine storm, and treatment modalities are being developed on inhibition of proinflammatory cytokines. We aimed to investigate the effects of anticytokine therapy on clinical improvement and the differences between anticytokine treatments. A total of 90 patients with positive COVID-19 polymerase chain reaction (PCR) test were divided into three groups, group I (n = 30) was given anakinra, group II (n = 30) was given tocilizumab, and group III (n = 30) was given standard treatment. Group I was treated with anakinra for 10 days; tocilizumab, intravenously, was given in group II. Group III patients were selected from those who did not receive any anticytokine treatment other than the standard treatment. Laboratory values, Glasgow coma scale (GCS), and PaO2/FiO2 values were analyzed on days 1, 7, and 14. The seventh-day mortality rates were 6.7% in group II, 23.3% in group I, and 16.7% in group III. In group II, the ferritin levels on the 7th and 14th days were significantly lower (p = 0.004), and the lymphocyte levels on the seventh day were significantly higher (p = 0.018). Examining the changes between the first intubation days, in the early period (seventh day), group I was found to be 21.7%, group II was 26.9%, and group III was 47.6%. We observed the positive effects of the use of tocilizumab on clinical improvement in the early period; mechanical ventilation requirement was delayed and at a lower rate. Anakinra treatment did not change mortality and PaO2/FiO2 rates. Mechanical ventilation requirements occurred earlier in the patients who were not receiving any anticytokine therapy. Studies with larger patient populations are needed to demonstrate the potential efficacy of anticytokine therapy. Ozkan F, Sari S. Comparison of Anakinra and Tocilizumab in Anticytokine Therapy in the Treatment of Coronavirus Disease-2019. Indian J Crit Care Med 2022;26(10):1091-1098.

Individualized High Dose Intravenous Anakinra Treatment is Safe and Effective in Patients with COVID-19 Associated Cytokine Storm Accompanying Cancer: A Retrospective Matched Study

Background: Severe COVID-19 course is associated with higher inflammatory state (cytokine storm) due to the excessive release of pro-inflammatory cytokines. Some preliminary results showed higher disease severity as well as mortality in patients with COVID-19 accompanying cancer. In this study, we aimed to evaluate the high dose intravenous anakinra treatment response and outcome in patients with severe and critically ill COVID-19 accompanying cancer. Method: This observational retrospective study was carried out at a tertiary referral center between 01.09.2021 and 01.02.2022 in Turkey. The study population consisted of two groups as follows; the patients receiving high dose intravenous anakinra (anakinra group) and the patients treated with standard of care (SoC, control group). Anakinra was started in patients who did not respond to steroid therapy at least two days or concomitantly with steroids in patients with higher risk and/or critical illness at admission. Results: Data of 146 patients in anakinra and 114 patients in control group were analyzed. Median±interquartile range (IQR) patient age was 71 (25) years, duration of hospitalization were 11 (12) days in anakinra group and 65.5 (23) years and 9 (7.3) days in control group, respectively. Fifty-seven (39 %) and 68 (59.6 %) patients had severe, 89 (61 %) and 46 (40.4 %) had critical disease in anakinra and control group, respectively. Overall, ICU admission was in 58 (39.7 %) and 25 (22 %), intubation was in 52 (35.6 %) and 13 (11.4 %) patients, 54 (37 %) and 27 (23.7 %) patients died in anakinra and control group, respectively. Malignancy frequency was 11 % (n=16) in anakinra group and 7 % (n=8) in the control group. In survival analysis, significantly lower survival rate was observed in patients with malignancy than those without in control group (Log-Rank: p=0.002) and patients with malignancy in control group compared to anakinra group (Log-Rank: p=0.013); but did not differ between patients with and without malignancy in anakinra group (Log-Rank: p=0.9). Conclusion: In our study, mortality was higher in patients with malignancy compared to those without control but not in anakinra group and also higher in patients receiving anakinra compared to SoC. Our study indicates that intravenous high dose anakinra treatment is safe and effective in patients with COVID-19 associated cytokine storm accompanying cancer.

Anakinra treatment of acute calcium deposits in hand and wrist

Acute calcium deposit (ACD) in the hand and wrist is a cause of acute pain due to crystal-induced soft-tissue inflammation. There are no standard management guidelines for this condition, which is frequently treated with non-steroidal anti-inflammatory drugs (NSAIDs), with variable efficacy, some patients presenting symptoms for several months. We retrospectively analyzed the results of all patients treated with anakinra for hand or wrist ACD in our department in 2020. We extracted data on treatment duration, pain, range of motion, skin erythema, hypervascularization, edema, and X-ray findings. Ten patients were treated for hand or wrist ACD with anakinra 100 mg per day for a mean 2.7 days. We observed rapid and significant improvement in pain, range of motion, local erythema and edema from day 2 and a decrease in skin temperature from day 3. Calcifications significantly decreased in size or disappeared in the majority of the patients. There were no adverse events or recurrences at 1 year’s follow-up. Anakinra was associated with significant clinical improvement after only two days’ treatment and may be considered to treat patients with hand or wrist ACD, especially in case of contraindications to NSAIDs or glucocorticoids. Further controlled studies are needed to confirm the present observations.

Comparison of Tocilizumab and Anakinra in the Treatment of COVID-19: A Single-Center Experience

Aim: The aim of this study was to examine whether a difference between endotracheal intubation, non-invasive mechanical ventilation, high flow oxygen therapy requirements and 28-day mortality rate in severe and critical coronavirus disease 2019 (COVID-19) patients receiving anakinra and tocilizumab treatment. Material and Methods: A total of 70 patients infected with COVID-19, who were treated with tocilizumab and anakinra from April 2020 to March 2021 at Karabük Training and Research Hospital, were recruited in this retrospective study. Data on patient demographics, comorbidities, treatments, clinical outcomes of the patients’ and hemogram findings were retrieved from hospital records. Results: The mean age of the patients was 61.34±11.8 years. Of the 70 patients, 12 (17.1%) were female and 58 (82.9%) were male. Severe and critical COVID-19 cases were evident in 48 (68.6%), and 22 (31.4%) patients, respectively. The mortality rate in 28 days was not statistically significantly different between the tocilizumab and anakinra groups (p=0.999). Both the necessity of high flow oxygen therapy and non-invasive mechanical ventilation were lower in the tocilizumab group than in the anakinra group (p&amp;lt;0.001, and p=0.002, respectively), while there was no statistically significant difference in the necessity of intubation between the two groups (p=0.999). The length of stay was also significantly shorter in the tocilizumab group (p=0.027). Conclusion: High flow oxygen therapy, non-invasive mechanical ventilation requirements, and length of stay were significantly lower than anakinra in the tocilizumab group. Excessive inflammatory response with cytokine storm features causes severe disease course and worsens prognosis in COVID-19.